| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration resistant prostate cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I study
The main aim of the Phase I study is to describe the safety and tolerability of abiraterone acetate and tildrakizumab when given in combination and to recommend a phase II dose (RP2D) for tildrakizumab, in combination with abiraterone.
Phase II study
The main aim of the Phase II study is to determine the antitumour activity of tildrakizumab (at RP2D) in combination with abiraterone in patients with mCRPC.
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| E.2.2 | Secondary objectives of the trial |
Phase I study:
- To investigate the pharmacodynamic (PD) effects of the combination of tildrakizumab and abiraterone in men with mCRPC.
- To characterize the pharmacokinetic (PK) profile of tildrakizumab given in combination with abiraterone in men with mCRPC.
- To identify molecular determinants of response and antitumour activity, of the tildrakizumab and abiraterone combination in men with mCRPC.
- To determine preliminary antitumour activity of tildrakizumab in combination with abiraterone in patients with mcRPC.
- To evaluate progression-free survival (PFS) in mCRPC patients receiving the tildrakizumab and abiraterone combination.
- To estimate the overall survival (OS) in mCRPC patients receiving the combination of tildrakizumab and abiraterone.
Phase II
- To evaluate PFS in mCRPC patients receiving tildrakizumab and abiraterone.
- To estimate the biochemical anti-tumour activity of tildrakizumab and abiraterone in mCRPC patients.
- To determine the pattern of radiologi |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent and be capable of cooperating with treatment & follow up.
2.Age ≥ 18 years
3.Histologically or cytologically proven adenocarcinoma of the prostate.
4.Metastatic castration resistant prostate cancer.
5.Documented prostate cancer progression as assessed by the investigator with one of the following:
a. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,
b. Progression of bone disease by PCWG3 bone scan criteria and/or,
c. Progression of PSA by PCWG3 PSA criteria and/or,
d. Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases.
6.Patients may have received have progressed after either enzalutamide or abiraterone treatment (having received a minimum of 12 weeks enzalutamide or abiraterone).
7.Ongoing androgen deprivation maintaining serum testosterone of less than 50 ng/dL (less than 2.0 nM) is mandatory.
8.Life expectancy of at least 12-weeks.
9.World Health Organisation (WHO) performance status of 0-2.
10. Able to swallow the study drug
11.Archival tissue must be available for research analysis
12.Patients must have disease that is amenable to biopsy and must be willing to undergo tumour biopsies.
13.Subjects must either have measurable disease as according to RECIST v1.1 or if the patient has bone-only metastases, a CTC count of ≥ 5/7.5 ml blood.
14. Haematological and biochemical indices within the ranges shown in 4.1.1 of the protocol. These measurements must be performed within one week of starting IMP |
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| E.4 | Principal exclusion criteria |
1.Patients with predominantly small cell or neuroendocrine differentiated prostate cancer
2.Prior therapy, including major surgery, chemotherapy, radium-223 or other anti-cancer therapy within 4 weeks prior to IMP administration. The use of bisphosphonates or RANK ligand inhibitors in patients with known osteopenia or osteoporosis or bone metastases is permitted. A single fraction of palliative radiation is permitted if at least 14-days before starting trial treatment.
3. Prior hormonal treatment
4.Prior limited field radiotherapy within the previous 2 weeks or wide field radiotherapy within the previous 4 weeks prior to IMP administration
5.Participation in another interventional clinical trial & any concurrent treatment with any investigational drug within 4 weeks prior to IMP
6.Any toxicities due to prior chemotherapy &/or radiotherapy that have not resolved to a NCI-CTCAE v4.02 Gr. ≤1 with the exception of chemotherapy induced alopecia & Gr.2 peripheral neuropathy
7.Clinical &/or biochemical evidence of hyperaldosteronism or hypopituitarism.
8.Use of drugs that are known strong CYP3A4 inducers and CYP2D6 substrates with a narrow therapeutic index. Seville orange or grapefruit products, and any herbal medications should be avoided 4 weeks prior to trial entry
9.Malabsorption syndrome or other condition that would interfere with enteral absorption
10.Intracerebral metastases
11.Any of the following cardiac criteria: •QT interval > 470 msec •Clinically important abnormalities including rhythm, conduction or ECG changes (left bundle branch block, third degree heart block) •Factors predisposing to QT prolongation including heart failure, hypokalemia, congenital long QT syndrome, family history of prolonged QT syndrome, unexplained sudden death (under 40) & concomitant medications known to prolong QT interval •Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, angina or congestive heart failure (NYHA ≥gr.2) in the last 6 months
12.Uncontrolled hypotension (systolic blood pressure <90mmHg &/or diastolic blood pressure <50 mmHg)
13.Uncontrolled hypertension on optimal medication (systolic blood pressure >180, diastolic blood pressure >100)
14.Patients with known history of adrenal insufficiency or mineralocorticoid excess
15.Patients with a significant history of liver disease (Child-Pugh B or C, viral or other hepatitis, current alcohol abuse or cirrhosis)
16.Serologically positive for hep. B, hep. C or human immunodeficiency virus (HIV).
17.At high medical risk because of non-malignant systemic disease including active infection
18.Known history of tuberculosis
19.Poorly controlled type 2 diabetes with HbA1C >7.5
20.Malignancy other than prostate cancer within 3 years of trial entry with the exception of adequately treated basal cell carcinoma. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy must have no evidence of that disease for at least 3 years & be deemed at negligible risk for recurrence, are deemed eligible
21.Immunocompromised patients including patients who have previously received organ transplants or are on long-term immunosuppression
22.Active or uncontrolled autoimmune disease requiring corticosteroid therapy
23.Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect interpretation of the results or renders the patients at high risk from treatment complications
24.Patients with female partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception or to sexual abstinence effective from the first administration of any of the study drugs throughout the trial and for 6 months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration. Men with pregnant or lactating partners must be advised to use barrier method contraception to prevent exposure of the foetus or neonate.
25.Prior bone marrow transplant
26.Extensive radiotherapy to greater than 25% of bone marrow within 8 weeks
27.Any other condition, which in the Investigator’s opinion would not make the patient a good candidate
28.Symptoms of COVID-19 and/or COVID-19 infection
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- In the Phase I study the primary outcome is to identify the DLTs during the DLT period, estimate the MTD, and identify the RP2D of tildrakizumab administered in combination with abiraterone at 1000 mg OD (with prednisolone 5 mg bid).
- In the Phase II study the primary objective is to determine the antitumour activity of tildrakizumab (at RP2D) in combination with abiraterone in men with mCRPC. Antitumour activity will be defined by response rate on the basis of the following outcomes. If any of the following occur, patients will be considered to have responded:
• PSA decline ≥ 50% criteria confirmed 4-weeks or later and/or,
• Confirmed soft tissue objective response by RECIST (v1.1) in patients with measurable disease and/or,
• ONLY for patients with detectable circulating tumour cell (CTC) count of ≥ 5/7.5ml blood at baseline, conversion of CTC count to <5/7.5ml blood nadir.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the safety and tolerability of the combination over the 28-day DLT period (one cycle). A safety review meeting will be carried out after recruitment of each dosing cohort throughout the study. In addition, there will be fortnightly safety meetings throughout the study.
Patients are evaluable for response if they meet all the eligibility criteria, undergo baseline and disease response assessment, are followed up for at least 2-cycles (8-weeks), and receive at least two cycles of treatment (defined as receiving at least 80% of the scheduled doses of abiraterone and two planned doses of tildrakizumab), unless treatment was ceased earlier due to disease progression (see antitumour activity response criteria in 23-1)). |
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| E.5.2 | Secondary end point(s) |
Phase I
- Measuring the impact of the downregulation of IL-23 signaling in tumour, also evaluating the downregulation of androgen receptor (AR), AR splice variants, and AR target genes.
-Determine the PK parameters (maximum blood concentration (Cmax), terminal elimination half-life (T1/2) and area under curve (AUC)) of tildrakizumab and abiraterone when dosed together.
-Determine biomarkers of response, including but not limited to PTEN loss, MYC amplification, and intra-tumour MDSC counts, in tumour biopsies from responders and non-responders.
-Response and progression will be determined using the same measures as that described for the primary objective of the Phase II study.
- PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria (RECIST v 1.1, PCWG3 bone scan criteria) or unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy).
-OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause).
Phase II
-PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria (RECIST v 1.1, PCWG3 bone scan criteria) or unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy).
-The following will be measured from date of addition of tildrakizumab to abiraterone:
• Time to PSA Progression
• Duration of PSA decline by ≥ 50%
• Maximum PSA decline
• Maximum percentage of PSA decline
-Time to radiological progression (RECIST 1.1 & PCWG3 Bone Scan criteria)
Radiologic PFS (rPFS)
-To assess the effects of tildrakizumab in combination with abiraterone on the number of circulating tumour cells (CTCs).
-Determine biomarkers of response, including but not limited to PTEN loss, MYC amplification, and intra-tumour MDSC counts, in tumour biopsies from responders and non-responders.
-Measuring the impact of the downregulation of IL-23 signaling in tumour, also evaluating the downregulation of androgen receptor (AR), AR splice variants, and AR target genes.
-Rate of CTC conversion from ≥ 5/7.5 ml blood to < 5/7.5 ml
-OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause).
-Causality and grading severity of each adverse event related to the tildrakizumab and abiraterone combination according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PD samples (biomarkers) will be analysed from all patients who receive at least one complete cycle of treatment and who provide blood, serum and tumour samples for PD analysis.
- PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria
- OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause).
- Documenting anti-tumour activity is a secondary objective of ACTION P1. Patients must receive 8-weeks of trial treatment to be evaluable for response, unless there is disease progression prior or treatment is stopped because of drug-related toxicity.
-AE collection commences from the time of consent until 28 days after last IMP |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the last visit of the last patient participating in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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